The immune system functions to defend the body against pathogenic bacteria, viruses and parasites. Immunity against foreign pathogens usually involves the complement system. The complement system is a cascade of 18 sequentially activated serum proteins which functions to recruit and activate other cells of the immune system, effect cytolysis of target cells and induce opsonization of foreign pathogens. Complement can be activated by the presence of either antibody/antigen complexes, as in the classical complement pathway, or microbial surfaces, as in the alternative complement pathway. Complement activation can also occur via the lectin complement pathway (LCP). Lectins are carbohydrate-binding proteins that recognize oligosaccharide structures present on cell surfaces, the extracellular matrix, and secreted glycoproteins. As shown in FIG. 1, these distinct activation pathways ultimately converge at the common enzymatic step of serum protein C3 cleavage to C3b and C3a. This in turn initiates the terminal steps of complement function including the cleavage of C5 to C5b and C5a and subsequent deposition of C5b-C9 onto the target cell membrane.
The LCP is an antibody-independent cascade that is initiated by binding of mannan-(or mannose) binding lectin (MBL) to cell surface carbohydrates on bacteria, yeasts, parasitic protozoa, and viruses (Turner MW, “Mannose-binding lectin: The pluripotent molecule of the innate immune system”, Immunol. Today, 1996;17:532-540). MBL (≈p600 kDa) is a member of the collectin protein family and is structurally related to the classical complement C1 subcomponent, C1q. Associated with MBL are two serine proteases, Mannose binding lectin associated serine protease, MASP-1 and MASP-2, which show in striking homology to the two C1q-associated serine proteases of the classical complement pathway, C1r and C1s (Thiel S, et al., “A second serine protease associated with mannan-binding lectin that activates complement”, Nature 1997;386:506-510). The selectivity of MBL sugar binding is: N-acetyl-D-glucosamine (GluNAc)>mannose>N-acetylmannosamine and fucose>maltose>glucose>>galactose and N-acetylgalactosamine (Thiel S, et al., “A second serine protease associated with mannan-binding lectin that activates complement”, Nature 1997;386:506-510; Turner M W, “Mannose-binding lectin: The pluripotent molecule of the innate immune system”, Immunol.Today, 1996;17:532-540). Binding of the MBL/MASP complex to cell surface carbohydrates activates the LCP, which in turn activates the classical complement pathway independently of C1q, C1r, C1s or antibodies (FIG. 1). Most if not all the carbohydrate moieties to which MBL binds are not normally expressed by unperturbed human tissue.